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ProteinDegradation&AAMetabolismProteinDegradation&AAMetab1ProteindegradationExtracellulardegradationIntracellulardegradation
ATP-independentoccursinlysosomes
ATP-dependent
i)N-endruleand“PEST”sequenceii)TheroleofUbiquitin(泛素）
iii)Proteasome（蛋白酶體）
iiii)HighlyregulatedProteindegradation2N-endruleAprotein's
half-life
correlateswithits
N-terminalresidue.ProteinswithN-terminalMet,Ser,Ala,Thr,Val,orGlyhavehalflivesgreaterthan20hours.ProteinswithN-terminalPhe,Leu,Asp,Lys,orArghavehalflivesof3minorlessN-endruleAprotein'shalf-lif3PESTproteinsIthasalsobeenfoundthatproteinsrichin
Pro(P),Glu(E),Ser(S)andThr(T),
called
PESTproteins,aremorerapidlydegradedthanotherproteins.PESTproteinsIthasalsobeen4UbiquitinUbiquitinisahighly-conserved,76residue(8.5kDa)proteinfoundwidelyineukaryotesProteinsaretaggedforselectivedestructionbyubiquitinAnisopeptidebondlinkstheterminalcarboxylofubiquitintothee-aminogroupofalysineresidueofa"condemned"protein.Threeenzymesareinvolved,designatedE1,E2&E3.UbiquitinUbiquitinisahighly5Protein-Degradation-and-教學(xué)講解課件Protein-Degradation-and-教學(xué)講解課件Proteasome20S
Largemultifunctionalproteasecomplexinthecytosolthatdegradesintracellularubiquitin-taggedproteins.(Justlikeabarrel)19S
regulatorysubunit(likeacap)This
regulatorycapcomplexrecognizesmulti-ubiquitinatedproteins,unfoldsthem,removesubiquitinchains,andprovidesapassagewayforthreadingunfoldedproteinsintothecorecomplex.26SProteasome20SLargemultifunct8Protein-Degradation-and-教學(xué)講解課件AAMetabolismAminoAcidDegradation1)Removalofthe-aminogroup
Deaminationi)L-AminoAcidOxidaseii)D-AminoAcidOxidaseiii)GlutamateDehydrogenase
TransaminationCombinedDeamination2)FatesofCskeletonketogenicaa&glycogenicaa3)DetoxificationandExcretionofAmmoniaAminoAcidSynthesisAAMetabolismAminoAcidDegrad10L-AminoAcidOxidase
L-aminoacidoxidase
isanenzymeinvolvedinaminoacidcatabolism.Itisaflavoprotein-containingenzymethatcatalyzesthereactionbelow,yieldingahydrogenperoxideintermediate.L-AminoAcidOxidaseL-amino11Protein-Degradation-and-教學(xué)講解課件GlutamatedehydrogenaseATP,GTPpromoteADP,GDPactivateGlutamatedehydrogenaseATP,GTTransaminase
Transaminaseisanameforacategoryofenzymesinvolvedinexchangeofanoxygenfroman-ketoacid(suchas-ketoglutarate)andanaminefromanaminoacid.Aminotransferasesutilizeacoenzyme－pyridoxalphosphateGPT&GOT
Notallaminoacidsundergotransamination(Thr,Pro,lys)TransaminaseTransaminaseis14TransaminasesLysinesidechainPyridoxalphosphateTransaminasesLysinesidechainTransamination
NH2|+HOOC-CH-R
O||HOOC-C-R
O||+HOOC-C-R
NH2|HOOC-CH-RTransaminationN16Protein-Degradation-and-教學(xué)講解課件Anexample-GOTAnexample-GOT18AminoAcid“X”
+-KetoglutarateGlutamate+-KetoAcid“X”-Ketoglutarate+NH4++NAD(P)HCombinedDeamination
TransaminationGlutamateDehydrogenase+NAD(P)+
AminoAcid“X”+-Ketog19FatesofC
skeletonGlucogenicKetogenic:Leu&LysBothglucogenicandketogenic:
Trp,Thr,Tyr,Ile,Phe(tttip)FatesofCskeletonGlucogenic20Protein-Degradation-and-教學(xué)講解課件MetabolicfatesofaminogroupsDietaryproteinCellularproteinAminoacidsCarbonskeletonNH4+Metabolicfatesofaminogroup22FatesofAmmoniumIonDirectexcretionAsn(Asn
synthetase)-inPlantsGln(Glnsynthetase)-inAnimalsUreaoruricacidFatesofAmmoniumIonDirectex23Glutaminesynthetase
-GenerationofBiologicallyActiveAmideNitrogen
GlutaminesynthetaseisadodecamerInanimals,theenzymeisakeyparticipantindetoxifyingammonia,
particularlyinthebrain,andinammoniaexcretioninthekidney.Accumulationofglutamateandglutaminedepletesa-ketoglutarate,
whichwouldinterferewiththecitricacidcycle.Glutaminesynthetaseistightlyregulated.Theamidenitrogenofglutamineisusedforthesynthesisofseveral
aminoacids,purineandpyrimidinenucleotides,andaminosugarsGlutaminesynthetaseGlutamineProtein-Degradation-and-教學(xué)講解課件RegulationofglutaminesynthetaseAllostericrergulation:
CumulativefeedbackInhibition
Eightspecificfeedbackinhibitors,whichareeithermetabolicendproducts
ofglutamine(tryptophan,histidine,glucosamine-6-phosphate,carbamoyl
phosphate,CTP,orAMP)orindicatorsofthegeneralstatusofaminoacid
metabolism(alanineorglycine)Bindtoanyofthesubunitsoftheenzymeandatleastpartiallyinhibitit.
Themoreinhibitorsthatbind,thegreatertheinhibition.Covalentmodification:
adenylylationregulatoryproteinPIIUT:stimulatedbyATP&a-ketoglutarate;inhibitedbyglutamineTyr397inactivatedRegulationofglutaminesyntheRegulationoftheactivityofE.coliglutaminesynthetase.GS:GlutaminesynthetaseAT:AdenylyltransferaseUT:UridylyltransferasePII:RegulatoryproteinRegulationoftheactivityofNitrogenexcretionNH4+UricacidUrea+uricacidNitrogenexcretionNH4+Uricaci28Protein-Degradation-and-教學(xué)講解課件Protein-Degradation-and-教學(xué)講解課件Protein-Degradation-and-教學(xué)講解課件RegulationoftheureacycleRegulationoftheureacycle32AminoAcidBiosynthesisPlantsandmicroorganismscanmakeall20aminoacidsandallotherorganismsneedNmetabolitesIntheseorganisms,glutamateisthesourceofN,viatransamination(aminotransferase)reactionsMammalscanmakeonly10ofthe20aminoacidsTheothersareclassedas"essential"aminoacidsandmustbeobtainedinthedietAllaminoacidsaregroupedintofamiliesaccordingtotheintermediatesthattheyaremadefromAminoAcidBiosynthesisPlants33Protein-Degradation-and-教學(xué)講解課件EssentialAminoAcidsAnyaminoacidforwhichthecorresponding-ketoacidisnotavailableasanintermediateofcarbohydratemetabolism.EssentialAminoAcidsAnyamino35ProteinDegradation&AAMetabolismProteinDegradation&AAMetab36ProteindegradationExtracellulardegradationIntracellulardegradation
ATP-independentoccursinlysosomes
ATP-dependent
i)N-endruleand“PEST”sequenceii)TheroleofUbiquitin(泛素）
iii)Proteasome（蛋白酶體）
iiii)HighlyregulatedProteindegradation37N-endruleAprotein's
half-life
correlateswithits
N-terminalresidue.ProteinswithN-terminalMet,Ser,Ala,Thr,Val,orGlyhavehalflivesgreaterthan20hours.ProteinswithN-terminalPhe,Leu,Asp,Lys,orArghavehalflivesof3minorlessN-endruleAprotein'shalf-lif38PESTproteinsIthasalsobeenfoundthatproteinsrichin
Pro(P),Glu(E),Ser(S)andThr(T),
called
PESTproteins,aremorerapidlydegradedthanotherproteins.PESTproteinsIthasalsobeen39UbiquitinUbiquitinisahighly-conserved,76residue(8.5kDa)proteinfoundwidelyineukaryotesProteinsaretaggedforselectivedestructionbyubiquitinAnisopeptidebondlinkstheterminalcarboxylofubiquitintothee-aminogroupofalysineresidueofa"condemned"protein.Threeenzymesareinvolved,designatedE1,E2&E3.UbiquitinUbiquitinisahighly40Protein-Degradation-and-教學(xué)講解課件Protein-Degradation-and-教學(xué)講解課件Proteasome20S
Largemultifunctionalproteasecomplexinthecytosolthatdegradesintracellularubiquitin-taggedproteins.(Justlikeabarrel)19S
regulatorysubunit(likeacap)This
regulatorycapcomplexrecognizesmulti-ubiquitinatedproteins,unfoldsthem,removesubiquitinchains,andprovidesapassagewayforthreadingunfoldedproteinsintothecorecomplex.26SProteasome20SLargemultifunct43Protein-Degradation-and-教學(xué)講解課件AAMetabolismAminoAcidDegradation1)Removalofthe-aminogroup
Deaminationi)L-AminoAcidOxidaseii)D-AminoAcidOxidaseiii)GlutamateDehydrogenase
TransaminationCombinedDeamination2)FatesofCskeletonketogenicaa&glycogenicaa3)DetoxificationandExcretionofAmmoniaAminoAcidSynthesisAAMetabolismAminoAcidDegrad45L-AminoAcidOxidase
L-aminoacidoxidase
isanenzymeinvolvedinaminoacidcatabolism.Itisaflavoprotein-containingenzymethatcatalyzesthereactionbelow,yieldingahydrogenperoxideintermediate.L-AminoAcidOxidaseL-amino46Protein-Degradation-and-教學(xué)講解課件GlutamatedehydrogenaseATP,GTPpromoteADP,GDPactivateGlutamatedehydrogenaseATP,GTTransaminase
Transaminaseisanameforacategoryofenzymesinvolvedinexchangeofanoxygenfroman-ketoacid(suchas-ketoglutarate)andanaminefromanaminoacid.Aminotransferasesutilizeacoenzyme－pyridoxalphosphateGPT&GOT
Notallaminoacidsundergotransamination(Thr,Pro,lys)TransaminaseTransaminaseis49TransaminasesLysinesidechainPyridoxalphosphateTransaminasesLysinesidechainTransamination
NH2|+HOOC-CH-R
O||HOOC-C-R
O||+HOOC-C-R
NH2|HOOC-CH-RTransaminationN51Protein-Degradation-and-教學(xué)講解課件Anexample-GOTAnexample-GOT53AminoAcid“X”
+-KetoglutarateGlutamate+-KetoAcid“X”-Ketoglutarate+NH4++NAD(P)HCombinedDeamination
TransaminationGlutamateDehydrogenase+NAD(P)+
AminoAcid“X”+-Ketog54FatesofC
skeletonGlucogenicKetogenic:Leu&LysBothglucogenicandketogenic:
Trp,Thr,Tyr,Ile,Phe(tttip)FatesofCskeletonGlucogenic55Protein-Degradation-and-教學(xué)講解課件MetabolicfatesofaminogroupsDietaryproteinCellularproteinAminoacidsCarbonskeletonNH4+Metabolicfatesofaminogroup57FatesofAmmoniumIonDirectexcretionAsn(Asn
synthetase)-inPlantsGln(Glnsynthetase)-inAnimalsUreaoruricacidFatesofAmmoniumIonDirectex58Glutaminesynthetase
-GenerationofBiologicallyActiveAmideNitrogen
GlutaminesynthetaseisadodecamerInanimals,theenzymeisakeyparticipantindetoxifyingammonia,
particularlyinthebrain,andinammoniaexcretioninthekidney.Accumulationofglutamateandglutaminedepletesa-ketoglutarate,
whichwouldinterferewiththecitricacidcycle.Glutaminesynthetaseistightlyregulated.Theamidenitrogenofglutamineisusedforthesynthesisofseveral
aminoacids,purineandpyrimidinenucleotides,andaminosugarsGlutaminesynthetaseGlutamineProtein-Degradation-and-教學(xué)講解課件RegulationofglutaminesynthetaseAllostericrergulation:
CumulativefeedbackInhibition
Eightspecificfeedbackinhibitors,whichareeithermetabolicendproducts
ofglutamine(tryptophan,histidine,glucosamine-6-phosphate,carbamoyl
phosphate,CTP,orAMP)orindicatorsofthegeneralstatusofaminoacid
metabolism(alanineorglycine)Bindtoanyofthesubunitsoftheenzymeandatleastpartiallyinhibitit.
Themoreinhibitorsthatbind,thegreatertheinhibition.Cov
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